The references cited throughout the present application are not admitted to be prior art to the claimed invention.
Programmed Cell Death 1 (PD-1) is a 50-55 kDa type I transmembrane receptor originally identified by subtractive hybridization of a mouse T cell line undergoing apoptosis (Ishida et al., 1992, Embo J. 11:3887-95). A member of the CD28 gene family, PD-1 is expressed on activated T, B, and myeloid lineage cells (Greenwald et al., 2005, Annu. Rev. Immunol. 23:515-48; Sharpe et al., 2007, Nat. Immunol. 8:239-45). Human and murine PD-1 share about 60% amino acid identity with conservation of four potential N-glycosylation sites and residues that define the Ig-V domain. Two ligands for PD-1 have been identified, PD ligand 1 (PD-L1) and ligand 2 (PD-L2); both belong to the B7 superfamily (Greenwald et al., 2005, supra). PD-L1 is expressed on many cell types, including T, B, endothelial and epithelial cells. In contrast, PD-L2 is narrowly expressed on professional antigen presenting cells, such as dendritic cells and macrophages.
PD-1 negatively modulates T cell activation, and this inhibitory function is linked to an immunoreceptor tyrosine-based inhibitory motif (ITIM) of its cytoplasmic domain (Greenwald et al., supra; Parry et al., 2005, Mol. Cell. Biol. 25:9543-53). Disruption of this inhibitory function of PD-1 can lead to autoimmunity. For example, PD-1 knockout in C57B1/6 mice leads to a lupus-like syndrome, whereas in BALB/c mice it leads to development of dilated cardiomyopathy (Nishimura et al., 1999, Immunity 11:141-51; Okazaki et al., 2003, Nat. Med. 9:1477-83). In humans, a single nucleotide polymorphism in PD-1 gene locus is associated with higher incidences of systemic lupus erythematosus, type 1 diabetes, rheumatoid arthritis, and progression of multiple sclerosis. The reverse scenario can also be deleterious. Sustained negative signals by PD-1 have been implicated in T cell dysfunctions in many pathologic situations, such as tumor immune evasion and chronic viral infections.
T cell responses are essential to clear viral infection; however, antiviral T cell responses are often associated with immunopathology. PD-1 mediated negative regulation is an important mechanism to limit tissue damage during clearance of viral infection by pro-inflammatory T cells. For example, PD-1 knockout mice clear adenovirus infections more efficiently but suffered more severe liver damage (Isai et al., 2003, J. Exp. Med. 198:39-50). Unfortunately, many viruses or microbes exploit the inhibitory functions of PD-1 to evade host T cell immunity (Greenwald et al., supra; Sharpe et al., supra). Sustained exposure to viral or microbial antigens during chronic infection can drive T cells to terminal differentiation with reduced capacities to proliferate and perform cytotoxic functions. The phenomenon, termed T cell “exhaustion,” was first described in chronic infection of lymphocytic choriomeningitis virus (LCMV) in mice (Wherry et al., 2003, J. Virol. 77:4911-27; Zajac et al., 1998, J. Exp. Med. 188:2205-13). High-level expression of PD-1 was found to be associated with T cell dysfunctions in the LCMV model (Barber et al., 2006, Nature 439:682-7) and in human chronic viral infections, including HIV, HCV, HBV (reviewed in Sharpe et al., supra). Treatment of LCMV-infected mice with a monoclonal antibody to PD-L1, a treatment presumably blocking inhibitory signaling by PD-1, has shown therapeutic benefits of restoring multi-functions of exhausted T cells in mice (Barber et al., supra).
Host anti-tumor immunity is mainly affected by tumor-infiltrating lymphocytes (TILs) (Galore et al., 2006, Science 313:1960-4). Multiple lines of evidence have indicated that TILs are subject to PD-1 inhibitory regulation. First, PD-L1 expression is confirmed in many human and mouse tumor lines and the expression can be further upregulated by IFN-γ in vitro (Dong et al., 2002, Nat. Med. 8:793-800). Second, expression of PD-L1 by tumor cells has been directly associated with their resistance to lysis by anti-tumor T cells in vitro (Dong et al., supra; Blank et al., 2004, Cancer Res. 64:1140-5). Third, PD-1 knockout mice are resistant to tumor challenge (Iwai et al., 2005, Int. Immunol. 17:133-44) and T cells from PD-1 knockout mice are highly effective in tumor rejection when adoptively transferred to tumor-bearing mice (Blank et al., supra). Fourth, blocking PD-1 inhibitory signals by a monoclonal antibody can potentiate host anti-tumor immunity in mice (Iwai et al., supra; Hirano et al., 2005, Cancer Res. 65:1089-96). Fifth, high degrees of PD-L1 expression in tumors (detected by immunohistochemical staining) are associated with poor prognosis for many human cancer types (Hamanishi et al., 2007, Proc. Natl. Acad. Sci. USA 104:3360-5).
Vaccination is an effective method to shape the host immune system by expanding T or B cell populations specific for vaccinated antigens. The immunogenicity of vaccines is largely dependent on the affinity of host immune receptors (B-cell receptors or T-cell receptors) to antigenic epitopes and the host tolerance threshold. High affinity interactions will drive host immune cells through multiple rounds of proliferation and differentiation to become long-lasting memory cells. The host tolerance mechanisms will counterbalance such proliferation and expansion in order to minimize potential tissue damage resulting from vaccine-induced local immune activation. PD-1 inhibitory signals are part of such host tolerance mechanisms, supported by following lines of evidence. First, PD-1 expression is elevated in actively proliferating T cells, especially those with terminal differentiated phenotypes, i.e., effector phenotypes. Effector cells are often associated with potent cytotoxic function and cytokine production. Second, PD-L1 is important to maintain peripheral tolerance and to limit overly active T cells locally. Its expression is upregulated by IFN-γ and genetic knockout of PD-1 ligands in mice will incur susceptibility to diabetes in NOD background (Keir et al., 2006, J. Exp. Med. 203:883-95).
U.S. Pat. Nos. 6,808,710 and 7,101,550, issued to C. Wood and G. Freeman on Oct. 26, 2004 and Sep. 5, 2006, respectively, disclose methods for attempting to modulate an immune response by activating or inhibiting signaling of the PD-1 receptor using, for example, an antibody that binds PD-1.
Based on the observation that blocking PD-1 inhibitory signals at time of priming decreases immune cell responsiveness, U.S. Pat. No. 7,029,674, issued Apr. 18, 2006 to B. Carreno and J. Leonard, discloses methods to decrease activation of an immune cell by contacting the cell with an agent that inhibits PD-1 signaling.
Various patent applications disclose production of anti-PD-1 antibodies and/or methods of enhancing immune responses with an agent (including an anti-PD-1 antibody) that interferes with PD-L1 binding and/or PD-1 signaling, including the following: U.S. Patent Application Publication Nos. US 2003/0039653, US 2004/0213795, US 2006/0110383, US 2007/0065427, US 2007/0122378; and PCT International Application Publication Nos. WO 2006/121168, and WO 2007/005874.